amfAR Symposium - Immunotherapy in Controlling HIV Infection
amfAR Symposium - Immunotherapy in Controlling HIV Infection
Although HAART restores immune function in patients with HIV infection, restoration is incomplete. Functional restoration is seen primarily in responses to antigens that are prevalent in HIV-infected persons. Immunization is required to restore responses to antigens that are not predictably present. As an exception, HIV-specific responses are also generally not restored despite the prevalence of these antigens. This may be because HIV replication specifically targets and either destroys or renders nonfunctional HIV-reactive CD4 T cells. Perhaps because HIV selectively targets HIV-reactive immune cells, therapeutic immunization strategies are particularly important areas of investigation in the treatment of HIV disease. Strategies designed to restore HIV-specific CD4 T-cell function must also enhance the activity of HIV-specific cytolytic T cells, since these are the likely key mediators of defense against HIV replication. Both active immunization strategies and treatment interruption strategies may enhance HIV-specific immune responses. Treatment interruption, by increasing exposure to HIV antigens through heightened HIV replication, also runs the risk of permitting sufficient HIV replication to damage HIV-responsive CD4 cells as well as enhancing the losses of other CD4 cell populations that may protect against opportunistic complications of HIV disease. Thus, treatment interruption strategies require careful and sophisticated monitoring and should not be tried at home.
HAART can restore a certain degree of immune function, as demonstrated by changes in both the phenotype and function of circulating lymphocytes. AIDS Clinical Trials Group (ACTG) protocol 315, a study of zidovudine, lamivudine, and ritonavir in patients with CD4 cell counts between 100 and 300/µL, exemplifies this effect of HAART.
The results of this trial and results of other studies, such as those from Autran and colleagues, show a 2-phase change in the numbers of circulating lymphocytes, beginning with a rapid first-phase increase in T cells of all populations. This rapid expansion takes place within the first 4 to 12 weeks of therapy and largely represents redistribution into the periphery of cells that were trapped in lymphoid tissue. The second-phase increase in peripheral CD4 T cells predominantly reflects increases in cells of the naive phenotype that can be identified by the presence of surface markers CD45RA and CD62L.
What predicts the magnitude of these increases? Since most of the increases occur in the first phase and are largely attributable to redistribution, it is not too surprising that baseline HIV RNA levels and the magnitude of RNA decreases before therapy are major predictors of the magnitude of the T-cell response. Patients with a high level of plasma HIV RNA usually have a more dramatic first-phase CD4 T-cell increase and, as a result, a larger 1-year increase in CD4 T lymphocytes than do patients with lower plasma viral loads before HAART is begun.
Another factor associated with the magnitude of CD4 T-lymphocyte restoration is the pretreatment CD4 cell slope. A study by Autran and colleagues shows that patients who have a modest CD4 cell decrease before HAART begins tend to have a modest CD4 cell increase with HAART. Conversely, those with a steep decrease in circulating CD4 cells before HAART tend to have a fairly dramatic increase with HAART. These findings are not surprising if the proximate mediator of CD4 cell changes is the inflammatory response generated by high-level viral replication. Interestingly, a preliminary review of the Glaxo-sponsored CNA3005 trial by Hill and coworkers revealed that patients with higher pretreatment CD4 T-cell counts were less likely to experience a CD4 T-cell increase after administration of HAART.
A somewhat surprising observation made by Wu and associates was that a slower decrease in plasma RNA levels during the first 2 weeks of HAART also correlates with a greater increase in circulating CD4 cells. I do not think that the slower RNA decrease actually causes the greater rise in CD4 cells. Instead, I suspect that both the slower RNA decrease and the larger CD4 cell increase probably reflect the relationship between an intrinsic cellular activation state that determines the rate of viral-induced cellular turnover (a likely component of the first-phase decay rate) and the magnitude of lymphocyte destruction in lymphoid tissue. Thus, those patients with faster viral decay are also those in whom lymphoid trapping results in greater cellular destruction, leaving fewer viable cells to redistribute into the circulation after viral replication is halted by application of antiviral therapies.
Although HAART restores immune function in patients with HIV infection, restoration is incomplete. Functional restoration is seen primarily in responses to antigens that are prevalent in HIV-infected persons. Immunization is required to restore responses to antigens that are not predictably present. As an exception, HIV-specific responses are also generally not restored despite the prevalence of these antigens. This may be because HIV replication specifically targets and either destroys or renders nonfunctional HIV-reactive CD4 T cells. Perhaps because HIV selectively targets HIV-reactive immune cells, therapeutic immunization strategies are particularly important areas of investigation in the treatment of HIV disease. Strategies designed to restore HIV-specific CD4 T-cell function must also enhance the activity of HIV-specific cytolytic T cells, since these are the likely key mediators of defense against HIV replication. Both active immunization strategies and treatment interruption strategies may enhance HIV-specific immune responses. Treatment interruption, by increasing exposure to HIV antigens through heightened HIV replication, also runs the risk of permitting sufficient HIV replication to damage HIV-responsive CD4 cells as well as enhancing the losses of other CD4 cell populations that may protect against opportunistic complications of HIV disease. Thus, treatment interruption strategies require careful and sophisticated monitoring and should not be tried at home.
HAART can restore a certain degree of immune function, as demonstrated by changes in both the phenotype and function of circulating lymphocytes. AIDS Clinical Trials Group (ACTG) protocol 315, a study of zidovudine, lamivudine, and ritonavir in patients with CD4 cell counts between 100 and 300/µL, exemplifies this effect of HAART.
The results of this trial and results of other studies, such as those from Autran and colleagues, show a 2-phase change in the numbers of circulating lymphocytes, beginning with a rapid first-phase increase in T cells of all populations. This rapid expansion takes place within the first 4 to 12 weeks of therapy and largely represents redistribution into the periphery of cells that were trapped in lymphoid tissue. The second-phase increase in peripheral CD4 T cells predominantly reflects increases in cells of the naive phenotype that can be identified by the presence of surface markers CD45RA and CD62L.
What predicts the magnitude of these increases? Since most of the increases occur in the first phase and are largely attributable to redistribution, it is not too surprising that baseline HIV RNA levels and the magnitude of RNA decreases before therapy are major predictors of the magnitude of the T-cell response. Patients with a high level of plasma HIV RNA usually have a more dramatic first-phase CD4 T-cell increase and, as a result, a larger 1-year increase in CD4 T lymphocytes than do patients with lower plasma viral loads before HAART is begun.
Another factor associated with the magnitude of CD4 T-lymphocyte restoration is the pretreatment CD4 cell slope. A study by Autran and colleagues shows that patients who have a modest CD4 cell decrease before HAART begins tend to have a modest CD4 cell increase with HAART. Conversely, those with a steep decrease in circulating CD4 cells before HAART tend to have a fairly dramatic increase with HAART. These findings are not surprising if the proximate mediator of CD4 cell changes is the inflammatory response generated by high-level viral replication. Interestingly, a preliminary review of the Glaxo-sponsored CNA3005 trial by Hill and coworkers revealed that patients with higher pretreatment CD4 T-cell counts were less likely to experience a CD4 T-cell increase after administration of HAART.
A somewhat surprising observation made by Wu and associates was that a slower decrease in plasma RNA levels during the first 2 weeks of HAART also correlates with a greater increase in circulating CD4 cells. I do not think that the slower RNA decrease actually causes the greater rise in CD4 cells. Instead, I suspect that both the slower RNA decrease and the larger CD4 cell increase probably reflect the relationship between an intrinsic cellular activation state that determines the rate of viral-induced cellular turnover (a likely component of the first-phase decay rate) and the magnitude of lymphocyte destruction in lymphoid tissue. Thus, those patients with faster viral decay are also those in whom lymphoid trapping results in greater cellular destruction, leaving fewer viable cells to redistribute into the circulation after viral replication is halted by application of antiviral therapies.